To the best of our knowledge, this study is the first one that specifically investigated the factors affecting the outcome of patients with metastatic triple-negative breast cancer (TNBC) receiving PLD. In this retrospective study, we analyzed the data of 39 patients with metastatic TNBC treated with PLD. In our results, DCR was 51.3%. Univariate analysis revealed that two out of the examined factors significantly affected DCR. These factors are chemosensitivity (chemosensitive tumor is better; 85.7% vs. 32%, respectively; P = .001) and the number of prior lines (two lines are better; 76.9% vs. 38.5%, respectively; P = .023). With multivariate analysis, chemosensitivity was the only independent predictor factor for DCR with an odds ratio of .095, 95% CI .015–.533, and P = .008.
The efficacy of PLD in metastatic TNBC is reported only in a Spanish study constructed by Martin-Romano et al. (2018), who enrolled only 15 patients with TNBC out of a total of 122 patients with MBC receiving PLD with gemcitabine [17]. They do not report the response rate for TNBC, but they report that ORR of 31.1% and DCR of 63.0% for all 122 patients. Although Martin-Romano et al. reported a higher response rate when compared to our result. This comparison is weak because they did not report the predictor factors of that response in TNBC. There is a case report paper published by Franchina et al. (2012), who reported the activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple-negative breast cancer with skin involvement [18]. This result may raise the future thinking of the study of pegylated liposomal doxorubicin in combination with gemcitabine in TNBC. Still, it does not serve our idea about the predictive factors for the response to PLD in patients with TNBC.
The median PFS for our patients is 7 months, with a 95% CI of 4.00–10.00 months. We found that the chemosensitivity is the only independent significant prognostic factor affected the median PFS; patients with chemosensitive tumor had more than double median PFS of those with chemoresistant tumor (12 months, 95% CI 7.80–16.21 for patients with chemosensitive tumor vs. 5 months, 95% CI 3.78–6.22 for those with a chemoresistant tumor, P = .002) with hazards ratio of .34, 95% CI .15–.80, and P = .013 by Cox regression analysis. As regards the effect of chemosensitivity on median PFS, there are reports on MBC in general, not specifically TNBC. Consistently with our findings, Al-Batran et al. [21] who reported a higher PFS in patients having a non-anthracycline-resistant disease than that in patients having an anthracycline-resistant disease (2.8, 95% CI 1.9–7.1 for the patient with anthracycline-resistant disease vs. 3.7, 95% CI 2.8–7.8 for the patient with the non-anthracycline-resistant disease; however, P value was not reported). Also, Keller et al. [22] indirectly concluded that the anthracycline resistance lowered median PFS; they stated that PLD is superior to vinorelbine in patients with non-anthracycline-resistant MBC (median PFS, 3.7 vs. 2.6 months, respectively; HR, 1.26; 95% CI 0.87–1.82) and comparable to vinorelbine in patients with anthracycline-resistant MBC (median PFS, 2.6 vs. 2.6 months, respectively; HR, 1.14; 95% CI 0.70–1.83). We used the term anthracycline-chemosensitive instead of non-anthracycline-resistant, which are quite similar. From the previous results, the anthracycline-chemosensitivity is the most important prognostic factor for patients with TNBC receiving PLD.
For our patients, the median OS is 12 months and 95% CI 10.80–13.20 months. There is a numerical, but not a statistically significant effect of chemosensitivity on the median OS in favor of chemosensitive disease (12 months, 95% CI 9.69–14.31) compared to chemoresistant disease (9 months, 95% CI 4.57–13.43; log-rank P = .052). Fiegl et al. [26] studied the prognostic factors in patients who received PLD for MBC. These factors were the number of metastatic sites, the number of prior chemotherapies, the prior endocrine therapy, and the prior anthracycline [26]. In contrast to our result, they reported that the occurrence of a greater number (≥ 4) of metastatic sites is the only independent risk factor for shorter OS (hazard ratio 2.78, 95% CI 1.75–4.42; P < .001) [26]. This contrast may be due to different patients’ subgroups regarding the number of metastatic sites (one site vs. two or more sites for our patients while less than four sites vs. four or more metastatic sites for their study). Also, this may be due to different biological subgroups, as mentioned by Battisti et al. (2018) who published a recent real-world review about systemic therapy for advanced TNBC. They reported that TNBC is classified into six molecular subtypes [8]. Battisti et al. reported results that may emphasize our findings. They found that patients with disease-free interval (DFI) more than 12 months (these patients are similar to a chemosensitive group in our study) are associated with better progression-free survival and overall survival when compared to those with DFI < 12 months [8]. The data about the prognostic factors for OS in patients with TNBC receiving PLD is still insufficient. This lack of data may be due to inadequate data about this group of patients in previous studies and a relatively small sample size of our research.
From our study and the prior studies, the severe cardiac toxicity (grade 3/4) of PLD is rare (0.0% in our study, the study of Al-Batran et al. [21], and the study of Keller et al. [22]; 1% in Harbeck et al. study [16]; and < 1% in Huober et al. study [15]). This rare incidence of severe cardiac toxicity enables the clinicians to administer higher cumulative doses of PLD than that of conventional doxorubicin. There is no reliable data about the cumulative dose of PLD, and most of the previous studies continued the treatment with it till progression or unacceptable toxicity. Al-Batran et al. [21] administered up to 12 cycles without recording any event of severe cardiac toxicity like our study in which the maximal number of the cycles was 18 cycles. Even more, Harbeck et al. [16] reached up to 24 cycles of PLD with only a 1% incidence of grade 3/4 cardiac toxicity. The dose-limiting of the PLD is palmar-plantar erythrodysesthesia (PPE). In our study, it was the most common adverse effect (33.3% for all grades and 10.3% for grade 3/4 toxicities). The occurrence of grade 3/4 PPE varies between the studies according to the reported data (39% by Harbeck et al. [16], 19% for Keller et al. [22], 6.4% by Al-Batran et al. [21], 6% by Huober et al. [15], and 1% by Fiegl et al. [26]). This variance may be due to different patients’ characteristics and PLD dosage and schedule. Hematological toxicity was less common than non-hematological toxicity. Grade 3/4 neutropenia (5%) was the most common, followed by anemia and leukopenia (4% for each). There is no treatment-related death.